A novel POLE mutation associated with cancers of colon, pancreas, ovaries and small intestine

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• 作者：Maren F. Hansen ; Jostein Johansen ; Inga Bj?rnevoll ; Anna E. Sylvander…
• 关键词：Colorectal cancer ; Polymerase epsilon ; POLE ; Germline mutation
• 刊名：Familial Cancer
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：14
• 期：3
• 页码：437-448
• 全文大小：2,135 KB
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• 作者单位：Maren F. Hansen (1) (2)
  Jostein Johansen (3)
  Inga Bj?rnevoll (2)
  Anna E. Sylvander (2)
  Kristin S. Steinsbekk (4)
  P?l S?trom (3) (5)
  Arne K. Sandvik (3) (6) (7)
  Finn Drabl?s (3)
  Wenche Sjursen (1) (2)
  
  1. Department of Laboratory Medicine, Children’s and Women’s Health, Faculty of Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway
  2. Department of Pathology and Medical Genetics, St. Olavs Hospital, Trondheim University Hospital, 7006, Trondheim, Norway
  3. Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway
  4. Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, 7491, Trondheim, Norway
  5. Department of Computer and Information Science, Faculty of Information Technology, Mathematics and Electrical Engineering, Norwegian University of Science and Technology, 7491, Trondheim, Norway
  6. Department of Gastroenterology, St. Olavs Hospital, Trondheim University Hospital, 7006, Trondheim, Norway
  7. Centre of Molecular Inflammation Research, Norwegian University of Science and Technology, 7491, Trondheim, Norway
  
• 刊物类别：Medicine
• 刊物主题：Medicine & Public Health
  Oncology
  Human Genetics
  Epidemiology
  
• 出版者：Springer Netherlands
• ISSN：1573-7292

文摘

In some families there is an increased risk for colorectal cancer, caused by heritable, but often unidentified genetic mutations predisposing to the disease. We have identified the likely genetic cause for disease predisposition in a large family with high burden of colorectal adenomas and carcinomas, in addition to extra-colonic cancers. This family had previously been tested for known cancer susceptibility genes, with negative results. Exome sequencing was used to identify a novel mutation, c.1373A>T (p.Tyr458Phe), in the gene for DNA polymerase epsilon catalytic subunit (POLE). This mutation is located in the active site of the exonuclease domain of the enzyme, and affects a residue that has previously been shown to be important for exonuclease activity. The first predisposing mutation identified in POLE (c.1270C>G, p.Leu424Val) was associated with colorectal cancer only, but another mutation with a broader tumour spectrum (c.1089C>A, p.Asn363Lys) has recently been reported. In the family described in the present study, carriers generally have multiple colorectal adenomas and cancer of colon, pancreas, ovaries and small intestine which represents an important broadening of the tumour spectrum of POLE mutation carriers. We also observe a large phenotypic variation among the POLE mutation carriers in this family, most likely explained by modifying variants in other genes. One POLE mutation carrier has a novel variant in EXO1 (c.458C>T, p.Ala153Val), which may contribute to a more severe phenotype. The findings in this study will have important implications for risk assessment and surveillance of POLE mutation carriers. Keywords Colorectal cancer Polymerase epsilon POLE Germline mutation